Hypermetabolism and catabolism of skeletal muscle mass persist for up to 2 years after burn injury, rendering patients vulnerable to injury and infection, retarding wound healing, reducing overall function and diminishing quality of life. We seek to understand the molecular pathways leading to muscle loss after burn injury in order to identify rational interventions to reduce wasting, speed recovery and improve survival. The main goal of this proposal is to explore the role of the myostatin family of muscle growth regulators in burn cachexia. To this end, we have assembled a multidisciplinary team of the PI, a molecular biologist and expert in muscle wasting, along with the world-leader in myostatin, a surgeon-scientist, and the director of one of the country's largest and busiest burn centers, with the ultimate goal of translating our findings to therapeutics. Our preliminary data in a mouse model of chronic burn wasting show that myostatin family signaling was increased in skeletal muscle in burn cachexia, that myostatin null mice exhibited enhanced survival after burn, and that administration of a myostatin inhibitor enhanced growth and recovery of muscle mass after burn injury. However, abolishing signaling from all myostatin-family ligands using a dominant negative receptor transgenic resulted in 100% mortality after burn injury. These data indicate the following overall hypothesis: Myostatin-family signaling contributes to muscle wasting after burn injury through growth-inhibitory and pro-catabolic effects on mature myofibers. Inhibiting myostatin-family signaling in the chronic catabolic state will accelerate recovery of muscle mass and preserve myofiber protein. However, myostatin-family induced catabolism in the immediate post-burn period is important for survival. The Specific Aims are: 1) to interrogate the mechanisms modulating myostatin and other ACVR2B ligand signaling and target genes in burn-induced muscle wasting;2) to test how global inhibition (genetic and pharmacologic) of myostatin or ACVR2B ligands in burn injury alters survival, muscle mass, SMAD and AKT activation, and proteolytic pathways;and 3) to test how manipulation of myostatin pathway signaling in individual myofibers alters myofiber size in normal muscle and in burn induced muscle wasting. PUBLIC HEALTH RELEVANCE: The studies will result in new insights into the molecular pathways by which myostatin and related ligands regulate muscle mass in normal physiology and in burn wasting. Furthermore, these studies are likely to identify novel genes involved in regulating muscle growth. They are essential pre-clinical studies for determining the potential clinical benefit of modulating myostatin for increasing survival and function after burn injury.